80
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 1
2,2'-Diethoxy-N-formylbenzhydrylamine (30) was obtained in 9370 yield (10.2 g), mp 170-171". Anal. (C1EHg1N03)C, H, N. 2,2'-Rialkoxybenzhydrylamines.-A suspension of 10 g of the appropriate N-formyl derivative in 50 ml of HC1 5yo was refluxed until a clear soln was obtd. hfter cooling the amine. €IC1 crystd. 2,2'-Dimethoxybenzhydrylamine~HCI (31)was obtained in 76% yield (7.8 g), mp 246-247'. Anal. (ClsH1&1N02) C, H, C1, N. 2,2'-Diethoxybenzhydrylamine.HCI (32) was obt.ained ill 85% yield (9.8 g), mp 239-240". Anal. (C1?H,2ClNO2) C, H,
mariner as the ether and CO oxygen storris iri tliil potelit nicotinic agent, ACh (Figure 1). Thus :ill ortho ring position would play a role a t the receptor compnra\)le to the c:trbonyl 0 atom.
c1, r;.
2,2'-Dialkoxybenzhydrylamides.-A soln of 0.01 mole of C1COCHzCl or BrCOCHBrCH3 in 10 ml of C6He was added over a period of 0.5 hr to a cold, stirred soln of 0.02 mole of the appropriate free berizhydrylamine in 10 ml of C6H6. The mixture was kept at 20-25' for 12 hr and then filtered. The filtrate was treated with an excess of the appropriate amine and the mixture was refluxed for 1.5 hr. After cooling, C6H.3 extract was filtered, washed twice with HZO, and dried (MgSOh), t,he solvent vias evaporated, and the hydrochloride was prepared (EtOH-ether). 2,2'-Dialkylbenzhydryl Esters.--8 soln of 0.01 mole of C1COCHzCl or BrCOCHBrCH3 in 10 ml of CsHB was added over a period of 0.5 hr t o a cold, stirred soln of 2.12 g (0.01 mole) of di-otolylcarbinol1° arid 0.89 ml (0.011 mole) of pyridine in 30 ml of C&. The mixture was stirred an addn 0.5 hr. It was filtered, the filtrate treated with an excess of the appropriate amine, and the mixture kept at 40-45" for 3 days. After cooling, it was treated as described in the above procedure.
Figure 1.-Spatial relationship between phenyl choliiie ether and acetylcholine postulated by Fukuil and predicted from this study.
FVe have reported extended Huckel AI0 calcul.dt'lolls on both ACh2 and nicotine3 in which 11e concluded that both nicotine and -4Ch can assume preferred conformations in which the pyridine S and carbonyl 0 atoms, respectively, are of similar distance from tlie onium groups iii each molecule (Figure 2 ) . The rolt
Acknowledgment.-We thank the Instituto Xacional de Farmacologia y Bromatologla for providing t'he necessary facilities for biological assays. This lvork was supported by a grant from the Consejo Naciorial de Investigaciones Cientificas y TBcnicas. (10) H. H. Hatt,
J. Chem.*Soc.,
1631 (1929).
Molecular Orbital Conformation of Phenyl Choline Ether LEMONT B KIER* Columbus Laboratoraes, Battelle JIemorzal Instztute, Columbus, Ohao AND JACK hI. GEORGL College of Medzczne, The Ohao State linzversaty, Columbus, Ohzo Recezved July 1 , 1970
Over the past decade a considerable amount of theoretical interest has been shown in the structural considerations of the nicotinic activity of a variety of molecules. Fukui studied a series of phenyl choline ethers, (I), using simple Huckel 110 calculations.
L
The study revealed that the substituent groups influence frontier electron density at the 0 and the superdelocalizability a t the ortho positions, and that these indices correlated with nicotinic activity. The suggestion was made that the 0 atom and the ortho position on the ring might be spatially related t o the onium group in the phenyl choline ethers in the same * To whom correspondence should be addressed. (1) F. Fukui, C. Nagata, and 8 . Imamura, Science, 184, 87 (1960).
Figure 2.-Spatial relationship between nicotine and acetylcholine in their predicted preferred conforrnation~.~
of the ether 0 iii the nicotinic activity of XCh is not evident' from this comparison,. since there is no iltom in nicotine th:Lt appears equivalent' t o the etlier 0 a t a receptor. The receptor equivalence of the pyridine N and the carbonyl 0 is certainly suggested from these studies. In a recent, study by Crow, et a,/., a series of ringsubstituted phenyl choline ethers was considered using simple Hucltel theory. The relationships between c d culated reactivity indices and nicot'inic activit'y revealed correlations only with the energy of t,he highest occupied 310 and the superdelocalizabilit,y at. the ring ortho positions. These findings agree with those of Fukui' except for the lack of a correlat'ion between a n oxygen reactivy index and activity. The suggestion arising from these results was that the aromatic ring int'eracts with the receptor, probably a t one of the ortho positions, to form a charge-transfer complex. A basic problem still remains with the phenyl choline ethers if the ortho ring position is t o be seriously considered as mimicking the carbonyl 0 of ACh ut the (2) L. B. Kier, M o l . I'harmacol., 3,487 (1967). (3) L . B . Kier, ibid.,4, 70 (1968). (4) J. Crow, 0. Wassermann, and W, Holland, J . .\fed. Chem., l a , 761 (1969).
Journal of Medicinal Chemistry, 1971, Vol. IL, No. 1 81
NOTES
nicotinic receptor. T h a t problem is whether a phenyl choline ether molecule has a conformational preference, as suggested by Fukui’ (Figure l),relating the features of both molecules. The subject of this study is therefore the prediction of the phenyl choline ether conformation.
fc
2.9
J
’I
Experimental Section The calcns were made using the extended Huckel theory first described by Hoffmann.5 The parameters employed were those suggested by Hoffmanns and employed by us.2 We have used this approach extensively to study the conformations of a wide variety of drug molecules with significant success in reproducing experimental values.Br7 In spite of its limitations, Hoyland has shown that extended Huckel theory is superior to currently available semiempirical &/IO methods for the prediction of conformation.8 I n this study we have calcd the conformation of unsubstituted phenyl choline ether, assuming that the ring substituents considered by Fukui’ and Crow4 were sufficiently removed from the aliphatic bonds studied that their influence on the conformational preference would be negligible. We have previously justified this assumption with a quantum mechanical argument.9 The +NRlea group was assumed to be staggered to the atoms bonded to the adjacent C and was held in this conformation throughout the study.
Results The series of calculations on phenyl choline ether have led to a minimum total energy corresponding to the conformation shown in Figure 3. As can be
0 N(CH,), I
l
4.7;
I
-2.9%
I
b.
Figure 3.-Calculated preferred conformation of phenyl choline ether (a) viewed down the CHZ-CHZ bond and (b) viewed down the O-CHt bond. ( 5 ) R. Hoffmann, J. Chem. Phys., 99, 1397 (1963). (6) L. B. Kier in “Fundamental Concepts in Drug-Receptor Interactions,” J. Danielli, J. hloran, a n d D . Triggle, E d . , Academic, New York, N. Y . , 1970. (7) L B. Kier in “Molecular Orbital Theory in Drug Research,” Academic, New York, N. Y., 1971. ( 8 ) J. R. Hoyland in “Molecular Orbital Studies in Chemical Pharmacology,” L. B. Kier, Ed., Springer-Verlag, New York, N . Y., 1970. (9) L. €3. Kier, J. Med. Chem., 11, 441 (1968).
I
(OC)
I
‘t\ 2.4i
/
i i . (‘>c-“) Figure 4.-Calculated
pattern of atoms in phenyl choline ether.
seen in Figure 3a, the 0, N relationship is predicted to be gauche, while the phenyl ring plane is perpendicular to the O-CH2 bond, as shown in Figure 3b. The distances separating the center of the onium group, the 0, and the nearest ortho ring position are shown in Figure 4. The N to ring ortho C atom distance is predicted to be 4.62 A, while the distanse presumed to be comparable in nicotine was 4.26 A3 and in the “nicotinic conformation” of ACh, 4.93 A.6 Discussion The calculations show that an ortho position of the P h ring can assume a distance from the onium group close to the range predicted for comparably charged atoms in nicotine and ACh. This finding supports the suggestion made by Fukui‘ and extends the conclusions reached by Crow, et aL4 From our study on nicotine3 and the failure to demonstrate an ether 0 index correlating with a ~ t i v i t ywe , ~ are lead to restate our previous conclusions that two features in a nicotinic molecule are primarily responsible for activity. The calculations in this study, however, show that the ether 0 in phenyl choline occupies a position relative to the onium group and a ring ortho position in the same molecule, roughly similar to the pattern predicted for the 3 comparable atoms in ACh in its “nicotinic” conformation. This ether 0 may not, however, be functional a t the nicotinic receptor. We conclude from this study that the predicted conformation of phenyl choline ether leads to structural features similar to those previously hypothesized to be the nicotinic pharmacophore. Acknowledgment.-This study was supported by Sational Institutes of Health Grant GM-16321.
